Blooms' syndrome is a cancer-prone disorder of humans that also has characteristics of a compound immunodeficiency. Blooms syndrome patients have low levels of mature T and B cell types, and an undescribed bone marrow precursor lymphocyte population. A single autosomal- recessive complementation group has been associated with Bloom's syndrome patients, primarily Ashkenazir Jews. Initial characterization of the defect suggests that DNA ligase I, one of the enzymes presumed to be involved in DNA replication and/or DNA repair, is mutant. This proposal focuses on several key questions regarding Bloom's syndrome. First, we propose to derive a molecular clone of the DNA ligase I gene type of mutation by DNA sequencing, to assess the prevalence of the mutant gene in the syndrome patients. SEcondly, we will determine the degree of normal versus abnormal gene regions from lymphoid cell lines and from bone marrow samples. The goal is to recombination pathway. We will determine whether mutant rearrangement of these gene families is directly responsible for the immunodeficiency of Blooms syndrome. Thirdly, we will investigate whether DNA ligase I is one of the essential enzymes used in the gene rearrangement pathway for Ig and TCR genes. Fourth, we will study the role of DNA ligase I in general chromosome stability in Blooms syndrome cells. Because Blooms's syndrome cells investigation of the molecular biology of this disease will be of great value for advancing our understanding of chromosome stability and maintenance, a property of eukaryotic cells that is frequently disrupted in the cancer state. A long range objective is to apply the molecular understanding of the DNA ligase I defect to some helpful purpose in the medical treatment of Blooms syndrome patients.
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